Synthesis and receptor affinities of some conformationally restricted analogs of the dopamine D1 selective ligand (5R)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol

Abstract

The synthesis of a structurally novel series of 6,6a,7,8,9,13b-hexahydro-5H-benzo[d]naphtho[2,1-b]azepines (2), conformationally restricted analogues of the dopamine D1 antagonist (5R)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin -7-ol (SCH 23390, 1c), is described. Affinity for D1 receptors was determined by competition for rat striatal binding sites labeled by [3H]SCH 23390; affinity for D2 receptors was similarly determined by competition experiments using [3H]spiperone. Compounds in this series having the B/C-trans ring junction (2b and related analogues), where the D ring is unequivocally fixed in an equatorial orientation, possess considerably more D1 receptor affinity and selectivity vs the D2 receptor than the conformationally mobile cis stereoisomers (2a), thus leading to the conclusion that axial substituents at the 4- or 5-positions of the benzazepine nucleus are detrimental to D1 receptor affinity. Resolution and X-ray analysis demonstrated that D1 receptor affinity was preferentially associated with the (-)-6aS,13bR enantiomer of 2b.